Stephen H. Petersdorf

Prognostic Significance of NPM1 Mutations in the Absence of FLT3–Internal Tandem Duplication in Older Patients With Acute Myeloid Leukemia: A SWOG and UK National Cancer Research Institute/Medical Research Council Report

PURPOSE Younger patients with acute myeloid leukemia (AML) harboring NPM1 mutations without FLT3-internal tandem duplications (ITDs; NPM1-positive/FLT3-ITD-negative genotype) are classified as better risk; however, it remains uncertain whether this favorable classification can be applied to older patients with AML with this genotype. Therefore, we examined the impact of age on the prognostic significance of NPM1-positive/FLT3-ITD-negative status in older patients with AML. PATIENTS AND METHODS Patients with AML age ≥ 55 years treated with intensive chemotherapy as part of Southwest Oncology Group (SWOG) and UK National Cancer Research Institute/Medical Research Council (NCRI/MRC) trials were evaluated. A comprehensive analysis first examined 156 patients treated in SWOG trials. Validation analyses then examined 1,258 patients treated in MRC/NCRI trials. Univariable and multivariable analyses were used to determine the impact of age on the prognostic significance of NPM1 mutations, FLT3-ITDs, and the NPM1-positive/FLT3-ITD-negative genotype. RESULTS Patients with AML age 55 to 65 years with NPM1-positive/FLT3-ITD-negative genotype treated in SWOG trials had a significantly improved 2-year overall survival (OS) as compared with those without this genotype (70% v 32%; P < .001). Moreover, patients age 55 to 65 years with NPM1-positive/FLT3-ITD-negative genotype had a significantly improved 2-year OS as compared with those age > 65 years with this genotype (70% v 27%; P < .001); any potential survival benefit of this genotype in patients age > 65 years was marginal (27% v 16%; P = .33). In multivariable analysis, NPM1-positive/FLT3-ITD-negative genotype remained independently associated with an improved OS in patients age 55 to 65 years (P = .002) but not in those age > 65 years (P = .82). These results were confirmed in validation analyses examining the NCRI/MRC patients. CONCLUSION NPM1-positive/FLT3-ITD-negative genotype remains a relatively favorable prognostic factor for patients with AML age 55 to 65 years but not in those age > 65 years.

NUP98/NSD1 and FLT3/ITD coexpression is more prevalent in younger AML patients and leads to induction failure: a COG and SWOG report

NUP98/NSD1 has recently been reported in association with poor outcome in acute myeloid leukemia (AML). Previous studies also observed a high overlap between NUP98/NSD1 and FLT3/ITD, raising the question as to whether the reported poor outcome is due to NUP98/NSD1 or caused by the co-occurrence of these 2 genetic lesions. We aimed to determine the prognostic significance of NUP98/NSD1 in the context of FLT3/ITD AML. A total of 1421 patients enrolled in 5 consecutive Childrens Oncology Group/Childrens Cancer Group and SWOG trials were evaluated. NUP98/NSD1 was found in 15% of FLT3/ITD and 7% of cytogenetically normal (CN)-AML. Those with dual FLT3/ITD and NUP98/NSD1 (82% of NUP98/NSD1 patients) had a complete remission rate of 27% vs 69% in FLT3/ITD without NUP98/NSD1 (P < .001). The corresponding 3-year overall survival was 31% vs 48% (P = .011), respectively. In CN-AML, patients with concomitant NUP98/NSD1 and FLT3/ITD had a worse outcome than those harboring NUP98/NSD1 only. In multivariate analysis, the dual NUP98/NSD1 and FLT3/ITD remained an independent predictor of poor outcome, and NUP98/NSD1 without FLT3/ITD lost its prognostic significance. Our study demonstrates that it is the interaction between NUP98/NSD1 and FLT3/ITD that determines the poor outcome of patients with NUP98/NSD1 disease.

Fate of Patients with Newly Diagnosed Acute Myeloid Leukemia Who Fail Primary Induction Therapy

The aim of this study was to describe the fate of patients with newly diagnosed acute myeloid leukemia (AML) who did not achieve an initial remission while being treated on a contemporary cooperative group trial. We analyzed the outcome of patients entered into S0106, a recently reported cooperative group trial for patients with newly diagnosed AML. A total of 589 eligible patients was treated, of whom 150 (25%) did not achieve a remission while on study and were available for further analysis. The 4-year survival rate for the entire cohort of 150 patients was 23%. Among the 64 patients who received an allogeneic hematopoietic cell transplant, the 4-year survival rate was 48% compared with 4% for the 86 patients who did not undergo transplantation. Among those transplanted, we could not detect a difference in outcome according to remission status, donor source, type of preparative regimen, or cytogenetic risk category. More than 20% of patients with newly diagnosed AML who fail induction therapy can still be cured, particularly if they are able to receive an allogeneic hematopoietic cell transplant. These results suggest that early HLA typing and donor identification are important components of the initial therapy of AML.

Prediction of CR following a second course of '7+3' in patients with newly diagnosed acute myeloid leukemia not in CR after a first course.

Prediction of CR following a second course of ‘7+3’ in patients with newly diagnosed acute myeloid leukemia not in CR after a first course

Co-expression of NUP98/NSD1 and FLT3/ITD is more prevalent in younger AML patients and leads to high-risk of induction failure: a COG and SWOG report

NUP98/NSD1 has recently been reported in association with poor outcome in acute myeloid leukemia (AML). Previous studies also observed a high overlap between NUP98/NSD1 and FLT3/ITD, raising the question as to whether the reported poor outcome is due to NUP98/NSD1 or caused by the co-occurrence of these 2 genetic lesions. We aimed to determine the prognostic significance of NUP98/NSD1 in the context of FLT3/ITD AML. A total of 1421 patients enrolled in 5 consecutive Childrens Oncology Group/Childrens Cancer Group and SWOG trials were evaluated. NUP98/NSD1 was found in 15% of FLT3/ITD and 7% of cytogenetically normal (CN)-AML. Those with dual FLT3/ITD and NUP98/NSD1 (82% of NUP98/NSD1 patients) had a complete remission rate of 27% vs 69% in FLT3/ITD without NUP98/NSD1 (P < .001). The corresponding 3-year overall survival was 31% vs 48% (P = .011), respectively. In CN-AML, patients with concomitant NUP98/NSD1 and FLT3/ITD had a worse outcome than those harboring NUP98/NSD1 only. In multivariate analysis, the dual NUP98/NSD1 and FLT3/ITD remained an independent predictor of poor outcome, and NUP98/NSD1 without FLT3/ITD lost its prognostic significance. Our study demonstrates that it is the interaction between NUP98/NSD1 and FLT3/ITD that determines the poor outcome of patients with NUP98/NSD1 disease.

NUP98/NSD1 and FLT3/ITD coexpression is more prevalent in younger AML patients and leads to induction failure

NUP98/NSD1 has recently been reported in association with poor outcome in acute myeloid leukemia (AML). Previous studies also observed a high overlap between NUP98/NSD1 and FLT3/ITD, raising the question as to whether the reported poor outcome is due to NUP98/NSD1 or caused by the co-occurrence of these 2 genetic lesions. We aimed to determine the prognostic significance of NUP98/NSD1 in the context of FLT3/ITD AML. A total of 1421 patients enrolled in 5 consecutive Childrens Oncology Group/Childrens Cancer Group and SWOG trials were evaluated. NUP98/NSD1 was found in 15% of FLT3/ITD and 7% of cytogenetically normal (CN)-AML. Those with dual FLT3/ITD and NUP98/NSD1 (82% of NUP98/NSD1 patients) had a complete remission rate of 27% vs 69% in FLT3/ITD without NUP98/NSD1 (P < .001). The corresponding 3-year overall survival was 31% vs 48% (P = .011), respectively. In CN-AML, patients with concomitant NUP98/NSD1 and FLT3/ITD had a worse outcome than those harboring NUP98/NSD1 only. In multivariate analysis, the dual NUP98/NSD1 and FLT3/ITD remained an independent predictor of poor outcome, and NUP98/NSD1 without FLT3/ITD lost its prognostic significance. Our study demonstrates that it is the interaction between NUP98/NSD1 and FLT3/ITD that determines the poor outcome of patients with NUP98/NSD1 disease.

Expression of topoisomerase (topo) II in adult acute myeloid leukemia (AML): Relationships to immunophenotype and treatment outcomes.

6564 Background: Anthracyclines used in the treatment of AML target topo II. Topo II α and β are genetically distinct with different expression (expr) patterns and cellular distribution. While topo IIα has been associated with increased proliferation and an adverse prognosis in AML, there is no information regarding topo IIβ. This study examined the relationships of topo IIα and β expr to immunophenotype (IP), multidrug resistant (MDR) phenotype and outcomes in adult AML. METHODS 230 pts with non-M3 AML by FAB criteria who received frontline ara-C/daunomycin (AD) therapy during the years 1992-98 on studies SWOG-9031, -9126, -9333 or -9500 were included (median age 63 years [18-88], WBC 29x109/L [0.8-274]). RT-PCR of RNA from marrow blasts was run with topo IIα and β specific primers (ABI PRISM 7900HT). Topo IIα and β expr in pts, normalized to internal standard β2-microglobulin, was measured by log (fold-change) relative to the Kasumi AML cell line. Treatment outcomes - complete response (CR), resistant disease (RD), and relapse-free and overall survival (RFS, OS) - were analyzed by logistic or Cox regression. RESULTS Topo IIα and β data were available for 211 pts. Topo IIα expr in pts ranged from 298-fold less to 91-fold more than in the Kasumi AML cell line, but was not significantly correlated with any pt characteristic, IP or treatment outcome in uni- or multivariate analysis. In contrast, topo IIβ ranged from only 9-fold less to 10-fold more than the cell line, but was associated with higher blast percentage in marrow (P=0.0001) or blood (P=0.0055); higher CD7 (P=0.0071); and lower CD14 (P<0.0001) and CD54 (P<0.0001) in multivariate regression analysis. In 105 pts with MDR data, topo IIβ was also inversely correlated with Rhodamine efflux (P<0.0001) and CD11c (P=0.0010). However after adjusting for prognostic factors, topo IIβ was not significantly related to any outcome, nor did topo IIβ interact significantly with any prognostic factors. CONCLUSIONS Topo IIβ expr reflects aspects of disease biology, such as highly proliferative disease (higher blasts), IP and MDR, and thus may not be an independent variable influencing outcome in adult AML pts treated with anthracycline-based therapy.